A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Inflammation involves a biphasic cycle of pro- and anti-inflammatory phases.
• Interleukin-1β (IL-1β) drives proinflammation, while Interleukin-37 (IL-37) acts as an anti-inflammatory cytokine.
• IL-1β and IL-37 are encoded within the same topologically associating domain (TAD).

Purpose of the Study:

• To investigate the regulatory mechanisms coordinating IL-1β and IL-37 expression within a shared TAD.
• To identify novel regulators of inflammation and trained immunity.
• To understand the role of long noncoding RNAs in inflammatory circuitries.

Main Methods:

• Identification and characterization of the long noncoding RNA AMANZI.
• Analysis of chromatin interactions and long-range contacts.
• Investigation of AMANZI's role in regulating IL-1β and IL-37 transcription.
• Assessment of the impact of the common variant rs16944 in AMANZI.

Main Results:

• AMANZI negatively regulates IL-1β expression and trained immunity by inducing IL-37 transcription.
• IL-37 activation is mediated by dynamic chromatin contacts, causing a temporal delay in anti-inflammatory responses.
• The AMANZI variant rs16944 influences this regulatory circuit, potentially predisposing to proinflammation or immunosuppression.

Conclusions:

• A chromatin-mediated biphasic circuit within a single TAD coordinates the expression of IL-1β and IL-37.
• AMANZI acts as a key regulator, linking chromatin dynamics to the control of opposing inflammatory states.
• This circuit provides new insights into the genetic predisposition to inflammatory and immunosuppressive conditions.